Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe, Av. Fernando Abril Martorell 106, 46026, Valencia, Spain.
Analytical Unit Platform, Medical Research Institute Hospital La Fe, Valencia, Spain.
World J Urol. 2022 Oct;40(10):2387-2398. doi: 10.1007/s00345-022-04136-7. Epub 2022 Sep 4.
Bladder cancer (BC) is among the most frequent malignancies worldwide. Novel non-invasive markers are needed to diagnose and stage BC with more accuracy than invasive procedures like cystoscopy. To date, no study has identified urine metabolites characteristic of all BC stages. To discover novel urine metabolomic profiles to diagnose and stage non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) patients using mass spectrometry-based metabolomics.
We prospectively recruited 198 BC patients and 98 age- and sex-matched healthy volunteers without evidence of renal or bladder condition confirmed by ultrasound, from whom we collected a first morning urine sample (before surgery in patients). In a discovery stage, an untargeted metabolomic analysis was conducted in urine samples of a selection of 64 BC patients (19 TaG1, 11 TaG3, 20 T1G3, 12 T2G3, 1 T2G2, 1 T3G3) and 20 controls to identify dysregulated metabolites. Next, after exhaustive multivariate analysis, confirmed dysregulated metabolites were validated in an independent cohort of 134 BC patients (19 TaG1, 62 TaG2, 9 TaG3, 15 T1G2, 16 T1G3, 4 T2G2, 9 T2G3) and 78 controls.
We validated p-cresol glucuronide as potential diagnostic biomarker for BC patients compared to controls (AUC = 0.79). For NMIBC, p-cresol glucuronide was valuable as staging biomarker (AUC = 0.803). And among NMIBCs, p-coumaric acid may be a potential specific staging biomarker for the TaG1 NMIBC; however, future validation experiments should be conducted once the precise version of the standard is commercially available. Remarkably, for MIBC we validated spermine as potential specific staging biomarker (AUC = 0.882).
Ours is the first metabolomics study conducted in urine of a thoroughly characterized cohort comprising all stages of NMIBC, MIBC and healthy controls in which we identified non-invasive diagnostic and staging biomarkers. These may improve BC management, thus reducing the use of current harmful diagnostic techniques.
膀胱癌（BC）是全球最常见的恶性肿瘤之一。需要新的非侵入性标志物来比膀胱镜等侵入性程序更准确地诊断和分期 BC。迄今为止，尚无研究确定所有 BC 分期的尿液代谢物特征。使用基于质谱的代谢组学方法，发现新的尿液代谢组图谱，以诊断和分期非肌肉浸润性（NMIBC）和肌肉浸润性（MIBC）患者。
我们前瞻性地招募了 198 名 BC 患者和 98 名年龄和性别匹配的健康志愿者，他们的肾脏和膀胱状况通过超声检查得到证实，我们从他们那里收集了第一份晨尿样本（在患者手术前）。在发现阶段，对 64 名 BC 患者（19 名 TaG1、11 名 TaG3、20 名 T1G3、12 名 T2G3、1 名 T2G2、1 名 T3G3）和 20 名对照者的尿液样本进行了非靶向代谢组学分析，以确定失调的代谢物。接下来，经过详尽的多变量分析，在 134 名 BC 患者（19 名 TaG1、62 名 TaG2、9 名 TaG3、15 名 T1G2、16 名 T1G3、4 名 T2G2、9 名 T2G3）和 78 名对照者的独立队列中验证了确认失调的代谢物。
与对照组相比，我们验证了对羟甲苯葡萄糖醛酸作为 BC 患者的潜在诊断生物标志物（AUC=0.79）。对于 NMIBC，对羟甲苯葡萄糖醛酸是有价值的分期生物标志物（AUC=0.803）。在 NMIBC 中，对香豆酸可能是 TaG1 NMIBC 的潜在特异性分期生物标志物；然而，一旦商业上获得标准的确切版本，应进行进一步的验证实验。值得注意的是，对于 MIBC，我们验证了精胺作为潜在的特异性分期生物标志物（AUC=0.882）。
这是第一项在经过彻底特征描述的包括 NMIBC、MIBC 和健康对照者所有阶段的队列的尿样中进行的代谢组学研究，我们在其中确定了非侵入性的诊断和分期生物标志物。这些可能会改善 BC 的管理，从而减少当前有害诊断技术的使用。
